The invention is drawn to methods and compositions for improving vascularization in mammals. Additionally, the compositions find use in wound healing.
Blood vessels are assembled by two processes known as vasculogenesis and angiogenesis. In vasculogenesis, a primitive vascular network is established during embryonic development from endothelial cell precursors called angioblasts. Angiogenesis involves preexisting vessels sending out capillary buds or sprouts to produce new vessels. Angiogenesis is an important process critical to chronic inflammation and fibrosis, to tumor cell growth, and to the formation of collateral circulation. Angiogenesis is involved in the normal process of tissue repair.
Tissue destruction, with damage to both parenchymal cells and stromal framework, occurs in inflammation. Repair to the tissue cannot be accomplished solely by regeneration of parenchymal cells, even in organs whose cells are able to regenerate. Attempts at repairing tissue damage occur by replacement of non-regenerated cells by connective tissue, which in time produces fibrosis and scarring.
After inflammation, repair of the tissue immediately begins. Fibroblasts and vascular endothelial cells began proliferating to form granulation tissue. Granulation tissue is characterized by the formation of new small blood vessels and the proliferation of fibroblasts. The new vessels are leaky and allow the passage of proteins and red blood cells into the extravascular space.
The inflammatory response is closely intertwined with the process of repair. Inflammation serves to destroy, dilute, or wall off the injurious agent. In turn, inflammation sets into motion a series of events that heal and reconstitute the damaged tissue. While repair begins during the early phases of inflammation, it reaches completion only after the injurious influence has been neutralized. During repair, the injured tissue is replaced by regeneration of native parenchymal cells, by filling of the defect with fibroblastic tissue, commonly known as scarring.
The inflammatory response occurs in the vascularized connective tissue. Circulating cells such as neutrophils, monocytes, eosinophils, lymphocytes, basophils, and platelets are involved. Connective tissue cells are the mast cells, which surround blood vessels, the connective tissue fibroblasts, and occasional resident macrophages and lymphocytes.
Progress has been made in transplant technology. New strategies on the horizon include the creation of man-made tissues or organs. However, the transplanted tissue or organ requires a blood supply. Thus, methods are needed for promoting vascularization in sites of interest.
Compositions and methods for stimulating and maintaining vascularization at predetermined sites in a host organism are provided. The method includes contacting the site with the matrix of the present invention wherein the matrix comprises denatured collagen, dextran and nitric oxide inhibitors. The matrix is useful in any setting where the host organism may benefit from an increased blood supply. Thus, the methods are useful in the treatment of diseases or conditions that benefit by increased blood circulation, in transplant therapies, wound healing and the like.